Role of Mitochondrial Reactive Oxygen Species in ageing and age-related diseases

Lead Research Organisation: Newcastle University
Department Name: Inst for Cell and Molecular Biosciences

Abstract

Ageing and age-related diseases such as Parkinson's disease (PD) are characterized by the accumulation of defective mitochondria that produce fewer molecules of ATP and leak more free radicals. Cells possess quality control mechanisms that remove defective mitochondria. Why and how defective organelles accumulate in aged individuals remains unknown. The most widely accepted explanation is that the age associated increase in levels of reactive oxygen species (ROS) is responsible for the deficient mitochondria found in aged tissues. In contrast to this however, boosting ROS levels has been shown to extend lifespan in animal models.

Recently, we have shown that elimination of damaged mitochondria prevents cellular senescence, whereas specifically increasing ROS produced by respiratory complex I protects mitochondrial function and extends lifespan in Drosophila melanogaster. We propose that signalling activated by ROS produced via complex I is required for turnover of damaged mitochondria. We hypothesize that when this signalling is interrupted during ageing (or in diseases where complex I are implicated such as PD) mitochondrial turnover is halted and ROS accumulate causing mitochondrial damage. These damaged mitochondria release mitochondrial DNA, proteins and metabolites, triggering inflammation, promoting oxidative damage and reducing autophagy via activation of Tor. Therefore, we propose that stimulating complex I activity, eliminating damaged mitochondria and preventing the leak of pro-inflammatory mitochondrial components will extend lifespan and protect against neurodegeneration.

The student will test the main hypothesis using three approaches: in vivo (Drosophila models of normal ageing and PD), in vitro (mammalian models of cellular senescence) and in silico (using RNA sequencing analysis). Upon completion, the student will have skills in molecular biology, imaging, physiology and big data analysis. This experience of diverse technologies and approaches will allow the student to pursue a successful scientific career.

Publications

10 25 50
 
Description Mayo Clinic - partnership via Joao Passos supervision. 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution Contributions to models in which the Senescence Associated Secretory Phenotype (SASP) is reduced by mitochondrial interventions.
Collaborator Contribution Complementary approaches (e.g.) RNA-Seq, animal models - further measurement of SASP reduction in transcription, and translatable effects in vivo. Supervisory guidance and advice regarding project direction.
Impact N/A
Start Year 2018
 
Description Cell Detectives public event, Centre for Life (Newcastle upon Tyne) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Members of the public attended the International Centre for Life in Newcastle upon Tyne, where we presented a range of microscopy equipment and techniques relating to our research in ageing, including hands-on activities and workshops, and take-home items such as wooden microscopes and cell models to promote excitement about science in school-age children. Between 200-400 people attended each day, with children of all ages showing an interest in using the microscopes and learning more about science. In particular those between 15-18 interested in pursuing science further at GCSE or A Level requested more information about the profession and what our work entailed.
Year(s) Of Engagement Activity 2019